Pharmaceutical formulations useful in the treatment of insomnia

ABSTRACT

There is provided a formulation suitable for transmucosal administration comprising a short acting hypnotic drug, which formulation provides a measurable plasma concentration of drug within 10 minutes of administration. The formulation is capable of providing sleep on demand, and preferably comprises particles of drug, for example zolpidem or a pharmaceutically-acceptable salt thereof and a mucoadhesion promoting agent, such as sodium carboxymethylcellulose, which particles of drug and mucoadhesive are presented upon the surface of larger carrier particles.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/402,580, filed Feb. 22, 2012, which is a continuation of U.S. patentapplication Ser. No. 13/184,016, filed Jul. 15, 2011, which is adivisional of U.S. patent application Ser. No. 11/666,361, filed Feb.11, 2008, which is the U.S. National Phase of International PatentApplication Serial No. PCT/GB2005/004147, filed Oct. 26, 2005, all ofwhich are hereby incorporated by reference in their entirety.

BACKGROUND OF THE INVENTION

This invention relates to new, fast acting pharmaceutical formulationscomprising short acting hypnotic agents that are useful in theshort-term treatment of insomnia, such as transient insomnia.

Insomnia is a common disorder characterized by difficulty in theinitiation and/or maintenance of sleep. Insomnia periodically affects30% of adults. Furthermore, more than 90% of the total population havetrouble with sleep at some point during their lives.

Inadequate sleep impairs quality of life and ability to functionnormally in a general sense. It often results in adverse personal,medical or psychiatric consequences, in addition to increasing the riskof accidents.

The disorder can be transient or chronic. Although isolated incidents ofshort-term insomnia may be caused by, for example, grief, stress, orshort-term exposure to substances that are known to impair sleep, manypatients who suffer from transient insomnia may experience the disorderregularly and/or periodically on a short-term basis.

In the treatment of short-term insomnia, consideration needs to be givento the potential side effects of the medicament employed, including anyassociated drug dependency. The practitioner also needs to be aware ofthe potential for undesirable absorption of drug taking place severalhours after administration, which may give rise to decreased alertnessand impaired psychomotor function during normal activity the followingday. In this respect, wherever possible, it is important to exposepatients only to short-term, or “on-demand”, use of the lowest effectivedose of any particular drug.

Zolpidem(N,N-dimethyl-2-(6-methyl-2-p-tolylimidazo-[1,2-a]pyridin-3-yl)acet-amide)is a short-acting sedative that is used in the short-term management ofinsomnia. The drug possesses a short half-life and produces no activemetabolites. It appears to act by binding to the benzodiazepine receptorcomponent of the GABA receptor complex and accordingly possesses similarproperties to the benzodiazepines. However, zolpidem has the generaladvantage of minimal anxiolytic, myorelaxant and convulsant properties.

Currently-available zolpidem formulations comprise doses of between 5and 10 mg of the drug in the form of its hemitartrate salt (see, forexample, British National Formulary, Volume 48, pages 174 and 175).These compositions are administered orally, typically before retiring,and rapidly disintegrate in the gastrointestinal tract to provide forsystemic absorption of drug.

Although zolpidem is rapidly absorbed from the gastrointestinal tract,its bioavailability is reported to be 70% following oral administration.Peak plasma concentrations are thereby typically reached within 1 and 5hours of oral administration using current formulations.

In view of this, onset of action can be delayed in many patients,leading to a frustrating lack of “on demand” sleep, in addition, in manycases, to undesirable residual effects (such as those mentionedhereinbefore) the following day. Equally importantly, in view of thefirst-pass and/or pre-systemic metabolism that is typically connectedwith oral administration, the use of currently-marketed zolpidemformulations is characterised by considerable inter- andintra-individual variability in terms of both onset of action andresidual effects (see, for example, Holm et al, Drugs (2000) 59, 865;Darcourt et al, J. Pharmacol., (1999) 13, 81; Terzano et al, Drug Safety(2003) 26, 261; Salva and Costa, Clin. Pharmacokinet. (1995) 29, 142:Drover et al, Clin. Ther. (2000) 22, 1443; and “Guidance for Industry;Labelling Guidance for Zolpidem Tablets”, US Department of Health andHuman Service (1997)).

Thus, there is a clear unmet clinical need for an improved formulationcomprising a short acting hypnotic agent, such as zolpidem, whichexhibits, in a consistent fashion, a more rapid, and preferably almostinstantaneous, onset of action (e.g. within minutes rather than hours),as well as fewer residual effects the following day.

A biphasic peroral dosage form comprising zolpidem has recently beendescribed in inter alia U.S. Pat. No. 6,514,531 B1. This system providesfor an initial immediate release phase to induce sleep as rapidly as ispossible with existing commercial formulations. This is followed by acontrolled-release phase with the objective of maintaining sleepfollowing induction. Other biphasic tablets comprising zolpidem aredisclosed in European patent application EP 1 260 216 A1.

U.S. Pat. No. 6,638,535 B2 also discloses sustained release pelletscomprising short acting hypnotic agents, such as zolpidem, zopiclone andzaleplon which provides for an in vitro release of less than 60% ofactive ingredient within the first 5 minutes of the in vitro test.

International patent application WO 00/16750 discloses a drug deliverysystem for the treatment of acute disorders by mucosal administration,in which the active ingredient is in microparticulate form and isadhered to the surface of larger carrier particles in the presence of abioadhesion and/or mucoadhesion promoting agent.

International patent application WO 03/059349 discloses oral dosageforms comprising inter alia zolpidem, in addition to a solubilityenhancer (e.g. a surfactant) and a spheronization agent (e.g. adistilled monoglyceride).

The skilled person would expect that transmucosal administration of anactive ingredient across the pulmonary, nasal or oral mucosa (e.g.sublingual administration) would give rise to an enhanced rate ofabsorption of that active into plasma (as compared to an oralformulation), and thereby result in a vastly increased bioavailabilityat an early stage following administration. In the treatment of insomniawith a short acting hypnotic agent such as zolpidem, such an enhancedrate of absorption might be expected to give rise to potential safetyproblems in patients that are sensitive to the drug, potentially givingrise to undesirable pharmacological effects, such as a more rapid onsetof sleep than is convenient (e.g. when preparing for sleep; see, forexample col. 2, lines 9 to 18 of U.S. Pat. No. 6,638,535 B2). Moreover,the skilled person would also expect such a rapid absorption tocompromise the duration of action of the relevant drug, and thereby theability to maintain sleep during the night, especially given that shortacting compounds are known to rapidly eliminated from plasma (see, forexample, col. 2, lines 19 to 31 of U.S. Pat. No. 6,638,535 B2).

Surprisingly, we have found that safe and reliable “on demand” sleepinduction (and maintenance) may be provided by way of a formulation asdescribed hereinafter.

SUMMARY OF THE INVENTION

According to a first aspect of the invention, there is provided apharmaceutical formulation suitable for transmucosal administrationcomprising a short acting hypnotic drug, which formulation provides ameasurable plasma concentration of that drug within 10 minutes ofadministration.

The measurement of drug plasma concentration may be achieved bytechniques that are well known in the art, for example as describedhereinafter.

However, as a guide, we have found that formulations suitable fortransmucosal administration are capable of providing a measurable plasmaconcentration of drug within 10 minutes of administration if, whenmeasured in a standard in vitro dissolution (paddle) apparatus accordingto the United States Pharmacopoeia, using a phosphate buffer at pH 6.8(USP) as dissolution medium, at least 50% of the active ingredient isreleased within minutes, preferably within 4 minutes, for example within3, or even 2, minutes. By the term “released” we mean that the activeingredient is released from the formulation and dissolved in thedissolution medium.

We have found that formulations according to the present invention arecapable of providing first measurable plasma drug concentrations with asurprising degree of consistency, as expressed as the coefficient ofvariation (CV: a statistical measure of the deviation of a variable fromits mean) for the time to first measurable plasma concentration.Observed CV values may be less than 50%, for example less than 40% forthis variable.

Thus, as formulations according to the present invention consistentlyprovide measurable plasma concentrations of drug within 10 minutes theyare effectively capable of providing for consistent “on demand” sleepinduction.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a graphical representation of plasma concentrations overtime of zolpidem produced by way of two sublingual table formulationsaccording to the present invention compared to plasma concentrationsover time of a commercially-available peroral formulation.

DESCRIPTION OF THE PREFERRED EMBODIMENT

Although the disclosure hereof is detailed and exact to enable thoseskilled in the art to practice the invention, the physical embodimentsherein disclosed merely exemplify the invention which may be embodied inother specific structures. While the preferred embodiment has beendescribed, the details may be changed without departing from theinvention, which is defined by the claims.

According to a further aspect of the invention, there is provided atransmucosal formulation suitable for providing sleep on demand, whichformulation comprises a short acting hypnotic drug.

By “sleep on demand”, we include that the formulation consistentlyinduces sleep, i.e. in at least 90% of cases (on an intra- and/orinter-patient basis), within 60 minutes, preferably within 45 minutes,more preferably within 30 minutes and especially within 20 (e.g. 15)minutes.

We have also found, very surprisingly, that formulations according tothe present invention are capable of providing rates of absorption ofdrug following administration that are not substantially different tothose that are observed in currently-available oral formulations. Inview of this, formulations according to the present invention arecapable of reducing or preventing inconveniently rapid onset of sleep,or other undesirable pharmacological effects that might be associatedwith rapid absorption, for example, in patients that are particularlysensitive to the relevant drug, as discussed hereinbefore.

In this respect, there is also provided a transmucosal formulationsuitable for providing sleep on demand, which formulation comprises ashort acting hypnotic drug, wherein the formulation provides for a timedifference between:

(a) the first measurable; and(b) the maximum measuredplasma concentration of drug following administration of theformulation, which time difference is within the range of about 50minutes to about 250 minutes, preferably about 55 minutes to about 230minutes, more preferably about 70 minutes to about 180 minutes andparticularly about 80 to about 160 minutes.

Equally surprisingly, we have also found that formulations according tothe present invention are capable of providing levels of drug at anappropriate time after administration and following sleep induction thatare not substantially different to those that are observed incurrently-available oral formulations. In view of this, formulationsaccording to the present invention are capable of maintaining adrug-induced sleep throughout the night.

In this respect, there is also provided a transmucosal formulationsuitable for providing sleep on demand, which formulation comprises ashort acting hypnotic drug, wherein the formulation provides for aplasma concentration of drug that is capable of maintaining sleep atleast about 3 hours after administration of the formulation, preferablyat least about 4 hours, more preferably at least about 5 hours andparticularly at least about 6 hours, after administration. In otherwisehealthy adult patients below the age of 60, plasma concentrations ofdrug that are capable of maintaining sleep are for example in the rangeof about 40 to about 100 ng/mL of plasma, for example about 50 to about90 ng/mL, such as about 60 to about 85 ng/mL.

Furthermore, formulations according to the present invention are capableof providing levels of drug at an appropriate time after administrationthat do not give rise to the undesirable residual effects mentionedhereinbefore the following day.

In this respect, there is also provided a transmucosal formulationsuitable for providing sleep on demand, which formulation comprises ashort acting hypnotic drug, wherein the formulation provides for aplasma concentration of drug that that does not result in decreasedalertness and/or impairment of psychomotor function in a patientfollowing sleep at least about 8 hours, such as about 7 hours afteradministration. In otherwise healthy adult patients below the age of 60,plasma concentrations of drug that are not capable of producing sucheffects, which effects may be objective (i.e. measurable by some test ormarker) or subjective (i.e. the subject gives an indication of, orfeels, such effects), are, for example, less than about 40 ng/mL ofplasma, for example less than about 30 ng/mL, such as less than about 25ng/mL.

It will be appreciated by the skilled person that the aforementionedplasma concentration ranges of active ingredient are exemplary of theaverage case and are likely to vary with the severity of the insomniathat is to be treated, as well as the age, weight, sex, renal function,hepatic function and response of the particular patient to be treated.There can, of course, be individual instances where plasmaconcentrations that are outside the ranges specified above may give riseto the stated effects, and such are within the scope of this invention.For example, for children or elderly patients, the aforementioned plasmaconcentration ranges may be approximately halved in order to produce (ornot produce) the relevant effect.

Transmucosal drug delivery may be provided over the pulmonary, the nasalor, more preferably, the oral, mucosa. Pulmonary transmucosal drugdelivery may be provided, for example, by way of a inhaler comprising apowder formulation that includes the active ingredient. Nasaltransmucosal drug delivery may be provided, for example, by way of anasal spray comprising a powder formulation that includes the activeingredient. Oral transmucosal delivery may be provided, for example, byway of a spray comprising a powder formulation that includes the activeingredient for spraying, for example, under the tongue, or by way ofeffervescent formulations or freeze-dried rapid melting tabletformulations, all of which are known to those skilled in the art.

However, we prefer that formulations according to the present inventionare in the form of sublingual tablets. Sublingual tablets that providefor sleep on demand may be prepared as described hereinafter.

According to a further aspect of the invention there is provided asublingual tablet formulation that is suitable for providing sleep ondemand, which formulation comprises particles of:

(a) a short acting hypnotic drug; and(b) a mucoadhesion promoting agent,which particles of components (a) and (b) are each presented, at leastin part, upon the surfaces of larger carrier particles.

It will be clear to the skilled person that formulations according tothe present invention will comprise a pharmacologically effective amountof short acting hypnotic drug (i.e. the “active” ingredient of theformulation). The term “pharmacologically effective amount” refers to anamount of active ingredient, which is capable of conferring the desiredtherapeutic effect on a treated patient, whether administered alone orin combination with another active ingredient. Such an effect may beobjective (i.e. measurable by some test or marker) or subjective (i.e.the subject gives an Indication of, or feels, an effect).

Short acting hypnotic drugs that may be employed in formulationsaccording to the present invention include zopiclone, zaleplon, indeplonor, preferably, zolpidem, and pharmaceutically acceptable salts of allof these. Also included are diastereomeric (e.g. enantiomeric) forms, aswell as active metabolites, of these compounds/salts.

Preferred salts of zolpidem that may be employed include hydrochloridesalts, methanesulphonate salts, tosylate salts, fumarate salts, sulphatesalts and tartrate salts, such as the hydrogen tartrate or thehemitartrate salt.

The active ingredient is preferably presented in the form ofmicroparticles, preferably with a weight based mean diameter of betweenabout 0.5 μm and about 15 μm, such as about 1 μm and about 10 μm. Theterm “weight based mean diameter” will be understood by the skilledperson to include that the average particle size is characterised anddefined from a particle size distribution by weight, i.e. a distributionwhere the existing fraction (relative amount) in each size class isdefined as the weight fraction, as obtained e.g. by sieving.

Microparticles of active ingredients may be prepared by standardtechniques, such as grinding, dry milling, wet milling, precipitation,micronisation, etc.

The amount of active ingredient that may be employed in a sublingualtablet may be determined by the physician, or the skilled person, inrelation to what will be most suitable for an individual patient. Thisis likely to vary with the severity of the condition that is to betreated, as well as the age, weight, sex, renal function, hepaticfunction and response of the particular patient to be treated.

Suitable quantities of active ingredient that may be employed in tabletformulations may be in the range 2 to 20% by weight based upon the totalweight of the formulation. More preferably, formulations may containbetween 4 and 17% by weight of active ingredient, and especially fromabout 5 to about 15%. The amount of active ingredient may also beexpressed as the absolute amount in a tablet formulation. In such acase, the total amount of active ingredient that may be present may besufficient to provide a dose of drug per tablet that is in the range 3to 15 mg, such as 4 to 13 mg and in particular between about 5 and about12 mg.

The above-mentioned dosages are exemplary of the average case; therecan, of course, be individual instances where higher or lower dosageranges are merited, and such are within the scope of this invention.

Tablet formulations described herein comprise one or more mucoadhesionpromoting agent and may thus facilitate the partial or complete adhesionof active ingredients to a biological surface, such as a mucosalmembrane.

In the context of the present invention, the terms “mucoadhesive” and“mucoadhesion” refer to adhesion or adherence of a substance to a mucousmembrane within the body. The skilled person will appreciate that theexpressions “mucoadhesion” and “bioadhesion” may often be usedinterchangeably. In this respect, the presence of a mucoadhesionpromoting agent helps facilitate the partial or complete adhesion ofsublingual tablets comprising active ingredient to the mucosal membraneunder the tongue.

A variety of substances known in the art can be used as mucoadhesionpromoting agents, for example polymeric substances, preferably with anaverage (weight average) molecular weight above 5,000. It is preferredthat such materials are capable of rapid swelling when placed in contactwith water and/or, more preferably, mucous, and/or are substantiallyinsoluble in water at room temperature and atmospheric pressure.

Examples of suitable mucoadhesion promoting agents include cellulosederivatives such as modified cellulose gum and, more particularly,hydroxypropylmethyl cellulose (HPMC), hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC), methyl cellulose, ethyl hydroxyethylcellulose, carboxymethyl cellulose and sodium carboxymethyl cellulose(NaCMC); starch derivatives such as modified starch, sodium starchglycolate and, more particularly, moderately cross-linked starch;acrylic polymers such as carbomer and its derivatives (Polycarbophyl,Carbopol®, etc.); polyvinylpyrrolidone; polyethylene oxide (PEO);chitosan (poly-(D-glucosamine)); natural polymers such as gelatin,sodium alginate, pectin; scleroglucan; xanthan gum; guar gum; polyco-(methylvinyl ether/maleic anhydride); and crosscarmellose (e.g.crosscarmellose sodium). Such polymers may be crosslinked. Combinationsof two or more blo/mucoadhesive polymers can also be used.

Suitable commercial sources for representative blo/mucoadhesive polymersinclude: Carbopol® acrylic copolymer (BF Goodrich Chemical Co,Cleveland, 08, USA); HPMC (Dow Chemical Co., Midland, Mich., USA); NEC(Natrosol; Hercules Inc., Wilmington, Del. USA); HPC (Klucel®; DowChemical Co., Midland, Mich., USA): NaCMC (Hercules Inc. Wilmington, Uk.USA); PLO (Aldrich Chemicals, USA); sodium alginate (Edward Mandell Co.,Inc., Carmel, N.Y., USA); pectin (BF Goodrich Chemical Co., Cleveland,Ohio, USA); crosslinked polyvinylpyrrolidone (Kollidon CL®, BASF,Germany, Polyplasaone XL®, Polyplasdone XL-10® and Polyplasdone INF-10®,ISP Corp., US); Ac-Di-Sol® (modified cellulose gum with a highswellability; FMC Corp., USA); Actigum (Mero-Housselot-Satia, Baupte,France); Satiaxana (Sanofi Biolndustries, Paris, France); Gantrez® (ISP,Milan, Italy); chitosan (Sigma, St Louis, Miss., USA); and sodium starchglycolate (Primojel®, DMV International BV, Netherlands, Vivastar®, J.Rettenmaier & Söhne GmbH & Co., Germany, Explotab®, Roquette America,US).

However, preferred mucoadhesion promoting agents that may be employed insublingual tablet formulations described herein include sodiumcarboxymethylcellulose.

Suitable forms of sodium carboxymethylcellulose include internallycrosslinked sodium carboxymethylcellulose, such as croscarmellose sodiumNF (e.g. Ac-Di-Sol® (FMC Corp., USA)).

Suitably, the amount of mucoadhesion promoting agent that is present ina tablet formulation may be in the range 0.1 to 25%, such as 0.5 to 15%and preferably 1 to 10% by weight based upon the total weight of theformulation. A preferred range is from 2 to 8%, such as from about 3.5to about 6.5% (e.g. about 5%) by weight.

Tablet formulations described herein may comprise one or more binderand/or disintegrating agent or “disintegrant”. A binder may be definedas any material that is capable of acting as a bond formation enhancer,facilitating the compression of the powder mass into coherent compacts.

A disintegrant may be defined as any material that is capable ofaccelerating to a measurable degree the disintegration/dispersion of atablet formulation, and in particular carrier particles, as definedherein. This may be achieved, for example, by the material being capableof swelling and/or expanding when placed in contact with water and/ormucous (e.g. saliva), thus causing the tablet formulations/carrierparticles to disintegrate when so wetted.

Suitable disintegrants include cross-linked polyvinylpyrrolidone,carboxymethyl starch and natural starch, and suitable binders includecellulose gum and, particularly, microcrystalline cellulose.

Preferred forms of microcrystalline cellulose include silicifiedmicrocrystalline cellulose (a mixture of microcrystalline cellulose anda small amount of colloidal silicon dioxide), such as ProSolv® (JRSPharma, Germany).

If present, binders and/or disintegrating agents are preferably employedin an amount of between 0.5 and 10% by weight based upon the totalweight of the formulation. A preferred range is from 1 to 8% (e.g. 5%),such as from about 2.0 to about 3.0% (e.g. about 2.25%) by weight.

It should be noted that sodium carboxymethylcellulose may function intablet formulations described herein both as mucoadhesion promotingagent and as a disintegrating agent.

Preferably, carrier particles for use in tablet formulations describedherein are of a size that is between about 50 and about 750 Tm, andpreferably between about 100 and about 600 Tm, such as between about 150Tm and about 400 Tm (e.g. about 200 Tm). Suitable carrier particlematerials include carbohydrates, e.g. sugar, mannitol and lactose;pharmaceutically-acceptable inorganic salts, such as sodium chloride,calcium phosphate, dicalcium phosphate hydrate, dicalcium phosphatedehydrate, tricalcium phosphate, calcium carbonate, and barium sulfate;polymers, such as microcrystalline cellulose, cellulose and crosslinkedpolyvinylpyrrolidone; or mixtures thereof. It is preferred that thecarrier particle material comprises a pharmaceutically-acceptablesubstance that is adequately soluble in water (e.g. exhibits asolubility of greater than 0.01 g/mL at room temperature and atmosphericpressure). Preferred materials thus include sugar alcohols and/orsugars, such as mannitol and lactose, or pharmaceutically-acceptableinorganic salts, such as sodium chloride.

Preferred carrier particle materials include mannitol, such asgranulated mannitol (Pearlitol 400 DC; Roquette, France) and spray-driedmannitol (Parteck M200; Merck, Germany).

Carrier particles preferably comprise an amount of between 50 and 95% byweight based upon the total weight of the formulation. A preferred rangeis from 60 to 90%, such as from 65 to 85% (e.g. between about 70 andabout 85%) by weight.

It is preferred that the relative sizes and amounts of the particles ofactive ingredient and the carrier particles that are employed aresufficient to ensure that the carrier particles may be at least about90% covered by the active ingredient, for example at least about 100%and up to about 200% (e.g. between about 130% and about 180%) covered.The skilled person will appreciate in this context that “100% coverage”of the carrier particles by the active ingredient means that therelative particle sizes and amounts of the relevant particles that areemployed are sufficient to ensure that the entire surface area of eachcarrier particle could be covered by the particles of the activeingredient notwithstanding that other ingredients (e.g. mucoadhesionpromoting agent) may also be present in a tablet formulation. Obviously,if other such ingredients are employed, then the actual degree ofcoverage of carrier particles by active ingredient may be less than theamounts specified above. 200% coverage means that there is sufficientparticles of active ingredient to cover the surfaces of the carrierparticles twice over, notwithstanding the presence of other ingredients.

It is surprising that such tablet formulations with greater than 90%theoretical coverage are effective. Based on current knowledge, theskilled person would understand that, in order to ensure rapiddissolution, it would be important to ensure that the relativesizes/amounts of active ingredient/carrier particles are sufficient toensure that 70% or less of the surfaces of the latter could be coveredby the former.

Tablet formulations may be prepared by standard techniques, usingstandard equipment known to the skilled person.

Active ingredient and other essential constituents mentionedhereinbefore may be combined with conventional pharmaceutical additivesand/or excipients used in the art for such preparations, and thereafterpreferably directly compressed/compacted into tablets. (See, forexample, Pharmaceutical Dosage Forms: Tablets. Volume 1, 2^(nd) Edition,Lieberman et al (eds.), Marcel Dekker, New York and Basel (1989) p.354-356 and the documents cited therein.)

Suitable further additives and/or excipients may thus comprise:

(a) surfactants or wetting agents, which may enhance that hydration ofthe active ingredient and carrier particles, resulting in fasterinitiation of both mucoadhesion and dissolution. If present, thesurfactant should be provided in finely dispersed form and mixedintimately with the active ingredients. Examples of suitable surfactantsinclude sodium lauryl sulphate, polysorbates, bile acid salts andmixtures thereof. If present, the surfactant may comprise between 0.3and 5% by weight based upon the total weight of the tablet formulation,and preferably between 0.5 and 3% by weight;(b) lubricants (such as sodium stearyl fumarate or, preferably,magnesium stearate). When a lubricant is employed it should be used invery small amounts (e.g. up to about 3%, and preferably up to 2%, byweight based upon the total weight of the tablet formulation);(c) flavourings (e.g. lemon, menthol or, preferably, peppermint powder),sweeteners (e.g. neohesperidin) and dyestuffs; and/or(d) other ingredients, such as carrier agents, preservatives and glidingagents.

The various ingredients may be dry mixed together in several ways for asufficient time in order to produce a mixture. This results in discreteparticles of drug and other relevant excipients, in particular themucoadhesion promoting agent, being presented on, and/or adhered to, thesurfaces of the carrier particles. Standard mixing equipment may be usedin this regard. The mixing time period is likely to vary according tothe equipment used.

Suitable compacting equipment includes standard tabletting machines,such as the Kilian SP300 or the Korsch EK0.

Irrespective of the foregoing, the tablet formulation should beessentially free (e.g. less than 20% by weight based on the total weightof the formulation) of water. It will be evident to the skilled personthat “premature” hydration will dramatically decrease the mucoadhesionpromoting properties of a tablet formulation and may result in prematuredissolution of the active ingredient.

Suitable final sublingual tablet weights are in the range 30 to 400 mg,such as 50 to 200 mg, for example 60 to 180 mg, more preferably betweenabout 70 and about 160 mg. Suitable final tablet diameters are in therange 4 to 10 mm, for example 5 to 9 mm, and more preferably about 6 toabout 8 mm. A preferred tablet weight is about 80 mg and a preferredtablet diameter is about 6 mm.

Wherever the word “about” is employed herein in the context ofconcentrations (e.g. of drug in plasma), timescales (e.g. in vitro drugrelease and measured/measurable drug plasma concentrations), dimensions(e.g. particle and tablet sizes), surface coverage (e.g. of carrierparticles by active ingredient), and amounts (e.g. absolute doses ofactive ingredient and relative amounts of individual constituents), itwill be appreciated that such variables are approximate and as such mayvary by ±10%, e.g. ±5%, from the numbers specified herein.

The tablet formulations described herein may be administeredsublingually by way of appropriate dosing means known to the skilledperson. A sublingual tablet may be placed under the tongue, and theactive ingredients absorbed through the surrounding mucous membrane.

The formulations according to the present invention are useful in thetreatment of insomnia and particularly transient insomnia. According toa further aspect of the invention there is provided a method oftreatment of insomnia which method comprises administration of aformulation according to the invention to a person suffering from, orsusceptible to, such a condition.

For the avoidance of doubt, by “treatment” we include the therapeutictreatment, as well as the symptomatic treatment, the prophylaxis, or thediagnosis, of a condition.

The formulations according to the present invention are easy andinexpensive to manufacture, and consistently enable the rapid uptake ofthe active ingredient through the mucosa, such as the oral mucosa. Thisenables “on demand” sleep, which is achievable before retiring,following an interruption of sleep, or in other situations when rapidsleep induction is desired. Most usefully, formulations according to thepresent invention are capable of providing this effect, whilst at thesame time reducing or preventing inconveniently rapid onset of sleep in,for example, patients that are particularly sensitive to the relevantdrug.

Furthermore, formulations according to the present invention are capableof maintaining a drug-induced sleep throughout the night, whilst at thesame time preventing or reducing the post-sleep residual effectsmentioned hereinbefore.

Finally, the present invention enables these surprising effects to beachieved in a highly consistent manner, in which inter- andintra-individual variations are significantly reduced or eliminated,providing the physician and end user with a dosage form that is capableof providing far more reliable sleep, both in terms of induction andduration.

Formulations according to the present invention may also have theadvantage that they may be prepared using established pharmaceuticalprocessing methods and employ materials that are approved for use infoods or pharmaceuticals or of like regulatory status.

Formulations according to the present invention may also have theadvantage that they may be more efficacious than, be less toxic than, bemore potent than, produce fewer side effects than, be more easilyabsorbed than, and/or have a better pharmacokinetic profile than, and/orhave other useful pharmacological, physical, or chemical propertiesover, pharmaceutical formulations known in the prior art, whether foruse in the treatment of insomnia or otherwise.

The invention is illustrated by way of the following examples withreference to FIG. 1, which shows a comparison of plasma concentrationsof zolpidem produced by way of two sublingual tablet formulationsaccording to the present invention versus a commercially-availableperoral formulation.

Example 1 Preparation of Sublingual Tablets

Sublingual tablets comprising 5 mg and 10 mg of zolpidem hemitartratewere prepared as follows.

Zolpidem hemitartrate (Boehringer Ingelheim, Germany) was firstly groundfor 20 minutes in a ball mill.

The active ingredient was then accurately weighed out, along with theother excipients (see below), in appropriate proportions that wouldenable the production of tablets with the absolute amounts of variousIngredients mentioned below.

Pre-weighed quantities of zolpidem hemitartrate and mannitol (ParteckM200; Merck, Germany) were then mixed in a Turbula mixer for 96 hours.Then, pre-weighed quantities of silicified microcrystalline cellulose(ProSolv®; JRS Pharma, Germany), sodium carboxymethylcellulose(Croscarmellose Sodium NF; Ac-Di-Sol®; FMC Corp., USA), Neohesperidin DC(Exquim, Spain) and peppermint powder (Firmenich, Germany) were addedand mixing was continued for 30 minutes. Finally, a pre-weighed quantityof magnesium stearate (Peter Greven, Netherlands) was added and mixingcontinued for another 2 minutes.

The powder mixture was then compacted using a single punch press (KorschEK0) with 6 mm flat bevel edged punches, to produce tablets of a totalweight of 80 mg.

The absolute amounts of individual ingredients are as presented in thetable below.

In-process controls were employed (tablet weight, crushing strength,friability and disintegration time), with test samples being withdrawnthroughout the tabletting process. Tablets were packaged and labelledfor use in Example 2.

5 mg Tablet 10 mg Tablet Ingredient Amount (mg) Amount (mg) zolpidemhemitartrate 5.00 10.00 mannitol 65.00 60.00 silicified microcrystalline1.80 1.80 cellulose sodium 4.00 4.00 carboxymethylcelluloseneohesperidin 0.20 0.20 peppermint powder 3.00 3.00 magnesium stearate1.00 1.00 Total tablet weight 80.00 80.00

Example 2 Clinical Study

An open randomized three-period crossover single-b centre study wasdevised to evaluate the pharmacokinetic profile of the sublingualzolpidem 5 mg and 10 mg tablets prepared by way of Example 1 above, ascompared to a peroral zolpidem formulation (Stilnoct® 10 mg;Sanofi-Synthélabo, France).

The trial was a pharmacokinetic study in healthy male and femalevolunteers to test for dose proportionality as between the twosublingual tablet formulations. The pharmacokinetic profiles wereevaluated, focussing on bioavailability and time and rate of absorption.The study also included a subjective assessment of efficacy, i.e. thesubjects' perceived degree of sedation.

18 healthy subjects aged between 18 and 40 were used in this study.Signed informed consents were obtained in all cases.

Each of the three formulations were given to each of the 18 volunteers,in a random order, at three visits to the study centre (hereinafter“Visits 1, 2 and 3”). Visits 1 and 2 were followed by a wash-out periodof at least 2 days.

At a pre-study visit, the subjects underwent a full clinical examinationto assess medical history, undertake a physical examination, withroutine screens for haematology, clinical chemistry, drugs and alcohol.This pre-study visit was conducted no more than 14 days prior to Visit1.

Blood samples for determination of the concentration of zolpidem inplasma were collected on 14 occasions on each study day. Samples werecollected immediately before administration and at 5, 10, 15, 30, 45,60, 90, 120, 180, 240, 300, 360, 480 and 600 minute intervalsthereafter. Tolerability and safety parameters were followed during thestudy day. Subject-rated sedation scores by visual analogue scales wereassessed during each study day.

A safety follow-up visit, which included a physical examination, withroutine screens for haematology and clinical chemistry was performed nomore that 10 days after Visit 3.

Any of the following was regarded as a criterion for exclusion from thestudy:

1. the subject was overweight (i.e. with a body mass index of greaterthan 30);2. the subject was a smoker;3. if the subject had drank alcohol within the previous 24 hours;4. if the subject showed any evidence of drug abuse;5. if the subject had used a prescription medication within the previous14 days;6. if, in the investigator's judgement, the subject exhibited clinicallysignificant abnormalities at the screening examination or in thelaboratory test results; and7. If the subject was female and was either pregnant, breast feeding orwas of childbearing potential and was not using adequate birth control.

Subjects were free to discontinue their participation in the study atany time. A subject could be withdrawn from the study at any time at thediscretion of the investigator. Subjects were to be discontinued fromthe study in event of, for example:

1. unacceptable adverse events;2. non-compliance with the study protocol; or3. failure to attend study visits.

However, all subjects completed the study in accordance with theprotocol and none of the subjects were replaced.

Each subject received three single doses of each of the threeformulations. The study nurse made sure that the formulations wereadministered correctly, with the sublingual tablets administered deeplyunder the tongue with the subject remaining in a supine position for atleast ten minutes. The oral tablet was swallowed.

Confirmed eligible subjects were assigned a subject number in a strictlyconsecutive order. Each subject number was randomised to one of sixpossible treatment sequences (3×2×1) according to a computer generatedrandomisation list provided by the study statistician. Three subjectswere thus assigned to each treatment sequence.

In order to allow time for 10 hours of blood plasma sampling,administration of the study drug formulation took place at approximately0800 hours on the morning of each visit.

The subjects fasted overnight before each visit. Upon arrival at theclinic, the subjects had a standard breakfast, after which study drugwas administered. Standard meals were served during the study day, withlunch at 1200 hours and dinner at 1700 hours. Subjects had their mealsafter taking blood samples at 240 minutes and 480 minutes, and neverdirectly before blood sampling.

Blood samples (7 mL) were collected in heparinised Vacutainer® tubes.The samples were kept on ice and then centrifuged for 10 minutes at2000×g. The plasma was transferred into labelled plastic tubes andstored at −20° C. prior to analysis. The frozen plasma samples weretransported to Quintiles, Uppsala, Sweden, where the zolpidemconcentration in the samples was measured.

Pharmacokinetic variables were derived from the zolpidem plasmaconcentration time curve. The primary pharmacokinetic variable wasAUC_(0-t), i.e. the area under the zolpidem plasma concentration timecurve from 0 minutes to 600 minutes after administration of study drug.

To further evaluate the pharmacokinetic profile of the sublingualzolpidem formulations, the following secondary pharmacokinetic variableswere derived from the plasma concentration time curve:

(a) the area under the curve from 0 minutes extrapolated to infinity(AUC_(0-∞));(b) maximum plasma concentration (C_(max));(c) time for maximum plasma concentration (t_(max));(d) half-life of the active substance (t½);(e) first measurable plasma concentration (C_(first)); and(f) time to first measurable plasma concentration (t_(first)).

The primary efficacy variable was subject-rated sedation as measured ona VAS. The VAS consisted of a 100 mm non-graded scale between theextremes “completely awake” and “practically asleep”. The subjects wereto fill in the sedation scales immediately before administration ofstudy drug and at 30, 60, 90, 120, 150, 180, 210, 240, 270, 300, 330,360, 390, 420, 450, 480, 510, 540, 570 and 600 minutes afterwards. Ifthe subject fell asleep, the study nurse made a note of this in the casereport form.

Safety variables included adverse events reported and laboratoryassessments.

The recording of adverse events was made on each study visit and on thepost-study visit. Patients were also free to report adverse eventsbetween visits. Adverse events were to be registered by the reporting ofspontaneously mentioned symptoms and by open questioning. Theinvestigator and the medical/laboratory staff were also instructed torecord any adverse event that they observed during the investigation.

Plasma concentrations of zolpidem were determined by using HPLC withfluorescence detection. This analytical procedure is capable ofmeasuring concentrations of zolpidem in human plasma within the range1.0 to 400 ng/mL. Zolpidem and an internal standard Trazodone werepurified from human heparin plasma by solid phase extraction using BondElute C₁₈ cartridges, rinsed with water and eluted with methanol. Theeluate was injected onto a reversed phase C₁₈ LC column (150×4.6 mm, 5μm) with a mobile phase composed of acetonitrile:50 mM potassiumphosphate buffer at pH 6.0 (4:6, v/v) and determined by fluorescencedetection (excitation at 254 nm and emission at 400 nm).

The study was performed in accordance with Good Clinical Practise (GCP)and Good Laboratory Practise (GLP). In order to ensure the use ofstandard terminology, and the collection of accurate, consistent,complete and reliable data, the study was preceded by a training sessionfor the investigator and study nurses.

The study was regularly monitored by external monitors appointed by thestudy sponsor. Complete source data verification of all parameters wasperformed and the case report forms were thereafter collected from thestudy site. Data was checked for accuracy by proof-reading, entered intoa database, validated and analysed by the sponsor. All corrections andadditions were signed and dated by the investigator.

Log AUC and log dose adjusted AUC were analysed using the SASstatistical program PROC GLM (SAS Institute Inc., Cary, N.C., USA) withsubject, treatment and period as class variables. Differences betweentreatments were given as 90% confidence intervals. Equivalence, and doseproportionality, respectively, were considered proven if the 90%confidence interval for the difference between treatments/doses did notexceed ±20% (or the ratio was within 0.80 and 1.25).

The quality of the determination of zolpidem concentration wassatisfactory and within the quality control (QC) acceptance criteria of±15%. The lower limit of quantification was 1.00 ng/ml for zolpidem inhuman plasma. The mean accuracy of the assay as determined from theanalysis of QC samples was within ±10.0%.

Results

Pharmacokinetic data for all subjects are given as mean values in Table1.

TABLE 1 Non-compartmental pharmacokinetic parameters (mean and SD) ofzolpidem following sublingual and oral administration (n = 18). 5 mg 10mg PK Parameter sublingual sublingual Stilnoct ® AUC_(0-t) 14913.830855.5 26879.1 (min · ng/ml) (SD 6714.2) (SD 14446.7) (SD 14605.3)AUC_(0-∞) 16064.3 33466.2 30093.7 (min · ng/ml) (SD 7770.4) (SD 16682.5)(SD 18976.9) C_(first) 5.2 8.7 10.8 (ng/ml) (SD 2.8) (SD 5.8) (SD 11.5)t_(first) 6.4 6.4 47.5 (min) (SD 2.3) (SD 2.3) (SD 34.6) C_(max) 50.098.8 90.6 (ng/ml) (SD 20.8) (SD 32.7) (SD 35.1) t_(max) 92.5 122.5 176.7(min) (SD 42.8) (SD 58.3) (SD 79.6) t_(1/2) 2.57 2.56 2.58 (h) (SD 0.79)(SD 0.82) (SD 1.04)These results demonstrate bioequivalence between the 10 mg sublingualtablet and Stilnoct® (10 mg) for AUC_(0-t). Dose proportionality betweensublingual zolpidem 5 mg and 10 mg tablets for dose adjusted AUC_(0-t),was established.

Most surprisingly, the time to the first measurable plasma concentration(t_(first)) and the time to the maximum plasma concentration (t_(max))are significantly shorter for the 10 mg sublingual tablet, as comparedto Stilnoct® (p<0.0001 and 0.0165, respectively). See also FIG. 1 inthis regard. The difference in the slope of the absorption curves i.e.absorption rate, is not statistically significant (p=0.478). Meanabsorption rates are given in Table 2.

TABLE 2 Absorption rate (slope of absorption phase of concentration-timecurve) by treatment, mean (SD) (n = 18). 5 mg sublingual 10 mgsublingual Stilnoct ® (10 mg) 0.0344 0.0359 0.0315 (0.0108) (0.0135)(0.0206)The elimination half-life (t_(1/2)) of zolpidem was similar for the twosublingual tablets (2.57 and 2.56 hours, respectively), indicating thatthe elimination kinetics are linear. There was also no statisticallysignificant difference in t_(1/2) between the two sublingual tablets andStilnoct® (2.58 hours). Elimination rates are given in Table 3.

TABLE 3 Elimination rate (slope of elimination phase ofconcentration-time curve) by treatment, mean (SD) (n = 18). 5 mgsublingual 10 mg sublingual Stilnoct ® (10 mg) −0.0050 −0.0052 −0.0052(0.0014) (0.0021) (0.0019)

Subject-rated sedation VAS scores were assessed and compared betweentreatments. No significant differences in efficacy between treatmentswas found. However, after adjustment for period baseline VAS values(change from baseline) there was a statistically significant differencein mean VAS change from baseline between the sublingual 10 mg tablet andStilnoct® in favour of the former (p=0.0062).

The number of subjects asleep was observed during ten hours followingadministration of the study drug. With the sublingual 10 mg tablet, moresubjects were asleep at 90 minutes than for Stilnoct®.

To further assess and compare sleep after the different study drugadministrations, the following values were calculated:

(a) first time of sleep (i.e. sleep latency; mean per treatment);(b) total number of sleep episodes (i.e. the total number of 30 minuteepisodes any subject was asleep per treatment: there were 377 episodesaltogether); and(c) total sleeping time (mean per treatment).

TABLE 4 Additional sleep variables (n = 18) Sleep 5 mg 10 mg Stilnoct ®variable sublingual sublingual 10 mg First time of 100.6 85.0 95.6 sleep(39.6)    (31.3)    (38.3)    (mean min) Total number 81/377 101/377101/377 of sleep (21.5%) (26.8%) (26.8%) episodes (n/377 and %) Totalsleep 135.0 168.3 168.3 time (70.7)    (74.3)    (98.8)    (mean min)

For the sublingual 10 mg tablet and Stilnoct®, the total sleeping timeas well as the number of sleeping episodes were similar, indicating thatsubjects slept equally long and deeply after administration of the twostudy drugs. The first time of sleep, however, occurred earlier for thesublingual 10 mg tablet, indicating that the onset of hypnotic effect isearlier for sublingual zolpidem compared to the oral administration (seeTable 4).

In terms of safety, there were no unexpected or serious adverse eventsfor any of the study medications.

CONCLUSIONS

This study shows that sublingual zolpidem (10 mg) tablets arebioequivalent to a peroral zolpidem formulation (Stilnoct®; 10 mg), withregard to AUC_(0-t), AUC_(0-inf) and C_(max). The pharmacokineticanalysis further shows that the extent of absorption and bioavailabilityof zolpidem was linear throughout the studied dose interval. Inaddition, the initial absorption rate of sublingual zolpidem isunaffected by the dose, which indicates that the same time to onset ofeffect can be expected for both doses.

There were no statistically significant differences between doses fordose adjusted AUC and C_(max), and dose proportionality of sublingualzolpidem 5 mg and 10 mg was established. The linear increase of the AUCwith increased dose provides strong evidence for a similar extent ofabsorption of zolpidem after sublingual administration of the studieddoses in these subjects.

Dose proportionality of sublingual zolpidem (5 mg and 10 mg tablets) wasestablished, with t_(first) and t_(max) being significantly shorter forsublingual zolpidem. This demonstrated that an earlier absorption intothe blood stream is achieved compared to oral administration. There isno statistically significant difference in the rate of absorption forsublingual zolpidem and Stilnoct® 10 mg, assessed from the slope of theabsorption phase of the plasma time-concentration curves.

The lower inter- and intra-individual variability in the pharmacokineticparameters of sublingual zolpidem versus oral zolpidem in healthyvolunteers, suggest that the in vivo performance of the sublingualtablet is better.

There was a greater number of subjects falling asleep earlier afteradministration with sublingual 10 mg tablets, compared to the otherstudy treatments. The mean total sleeping time, as well as the number ofsleeping episodes was similar after treatment with sublingual 10 mgtablets and Stilnoct®.

These results indicate that formulations according to the presentinvention may be capable of providing, in a consistent fashion, sleep ondemand in insomnia patients.

The foregoing is considered as illustrative only of the principles ofthe invention. Furthermore, since numerous modifications and changeswill readily occur to those skilled in the art, it is not desired tolimit the invention to the exact construction and operation shown anddescribed. While the preferred embodiment has been described, thedetails may be changed without departing from the invention, which isdefined by the claims.

1. A pharmaceutical formulation suitable for transmucosal administrationcomprising a short acting hypnotic drug, which formulation provides ameasurable plasma concentration of drug within 10 minutes ofadministration.
 2. A formulation as claimed in claim 1, wherein, whenmeasured in a standard in vitro paddle apparatus according to the UnitedStates Pharmacopoeia, using a phosphate buffer at pH 6.8 (USP) asdissolution medium, at least 50% of the drug that is initially presentin the formulation is released within 5 minutes.
 3. A formulation asclaimed in claim 2, wherein the drug is released within 3 minutes.
 4. Atransmucosal formulation comprising a short acting hypnotic drug.
 5. Aformulation as claimed in claim 4, which is suitable for providing sleepon demand.
 6. A formulation as claimed in claim 1, wherein theformulation provides for a time difference between: (a) the firstmeasurable; and (b) the maximum measured plasma concentration of drugfollowing administration of the formulation, which time difference iswithin the range of about 80 minutes to about 160 minutes.
 7. Aformulation as claimed in claim 1, wherein the formulation provides fora plasma concentration of drug that is capable of maintaining sleep atleast about 6 hours after administration.
 8. A formulation as claimed inclaim 1, wherein the formulation provides for a plasma concentration ofdrug that does not result in decreased alertness and/or impairment ofpsychomotor function in a patient following sleep at least about 7 hoursafter administration.
 9. A formulation as claimed in claim 1, which issuitable for administration across the oral musosa.
 10. A formulation asclaimed in claim 9, which is a sublingual tablet.
 11. A formulation asclaimed in claim 10, which comprises particles of: (a) the short actinghynotic drug; and (b) a mucoadhesion promoting agent, which particles ofcomponents (a) and (b) are each presented, at least in part, upon thesurfaces of larger carrier particles.
 12. A formulation as claimed inclaim 1, wherein the drug is zolpidem or a pharmaceutically acceptablesalt thereof.
 13. A formulation as claimed in claim 12 wherein the saltis zolpidem hemitartrate.
 14. A formulation as claimed in claim 1,wherein the drug is in the form of microparticles.
 15. A method oftreatment of insomnia which method comprises the sublingualadministration of a pharmaceutical formulation comprising zolpidem or apharmaceutically acceptable salt thereof, to a patient suffering from,or susceptible to, insomnia, and wherein said sublingual administrationprovides for: (i) a measurable plasma concentration of zolpidem within10 minutes of administration; (ii) a time difference between; (1) thefirst measurable plasma concentration of zolpidem; and (2) the maximummeasured plasma concentration of zolpidem following administration ofthe formulation, which time difference is within the range of about 80minutes to about 160 minutes; and (iii) a plasma concentration ofzolpidem that is capable of maintaining sleep for at least about 6 hoursafter sublingual administration.